Submissions for variant NM_001384140.1(PCDH15):c.593C>T (p.Pro198Leu)

gnomAD frequency: 0.00024  dbSNP: rs145232643

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001248205	SCV000063457	uncertain significance	not provided	2019-05-09	criteria provided, single submitter	clinical testing	The p.Pro198Leu variant in PCDH15 has been previously identified by our laboratory in three individuals with hearing loss who did not have a second PCDH15 variant. This variant has also been identified in 0.03% (50/128964) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Pro198Leu variant is uncertain, available data suggest that it is more likely to be benign. PM2_Supporting, BP4.
Illumina Laboratory Services, Illumina	RCV000378841	SCV000363239	uncertain significance	Usher syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248205	SCV001421675	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the PCDH15 protein (p.Pro198Leu). This variant is present in population databases (rs145232643, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 46509). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001248205	SCV001768153	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Observed in a patient with retinitis pigmentosa who was also heterozygous for variants in other genes in published literature (PMID: 28912962); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28912962)
Fulgent Genetics, Fulgent Genetics	RCV002504908	SCV002815778	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2022-03-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001248205	SCV004225245	uncertain significance	not provided	2022-04-12	criteria provided, single submitter	clinical testing	BP4, PM2_supporting
Ambry Genetics	RCV004018895	SCV004998855	uncertain significance	Inborn genetic diseases	2024-09-08	criteria provided, single submitter	clinical testing	The c.593C>T (p.P198L) alteration is located in exon 6 (coding exon 5) of the PCDH15 gene. This alteration results from a C to T substitution at nucleotide position 593, causing the proline (P) at amino acid position 198 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001276789	SCV001463338	uncertain significance	Usher syndrome type 1F	2020-09-16	no assertion criteria provided	clinical testing